Acute Exenatide Therapy Attenuates Postprandial Vasodilation in Humans with Prediabetes: A Randomized Controlled Trial

Abstract

Background: The state of prediabetes comprises atherosclerotic changes leading to decreased vascular function in humans. This study examined the effects on incretin mimetics on vascular physiology in the prediabetic postprandial state. Methods: Fifteen obese adults with prediabetes participated in a randomized, crossover, double-blinded trial comparing the postprandial effects of exenatide, saxagliptin, and placebo on peripheral vasodilation. All studies utilized a standardized high-fat meal. Resting and peak forearm blood flow (FBF) were measured via strain gauge venous occlusion plethysmography, and makers of vascular dysfunction were measured in plasma. Results: Exenatide attenuated resting FBF at 3 hr (P = 0.003) and 6 hr (P = 0.056) postmeal, compared to placebo. Nonsignificant reductions in resting FBF were observed between saxagliptin and placebo at the same time points. No group differences were observed for peak FBF, plasma nitrotyrosine, and plasma 8-iso-prostaglandin F2alpha. A transient increase in plasma triglyceride was abated in the exenatide group, when compared to saxagliptin and placebo groups. Only exenatide group showed no significant upsurge in plasma insulin. Plasma-free fatty acids significantly declined in all three groups, although less markedly for exenatide. Postmeal glucose increased at 2 hr with placebo and saxagliptin, but simultaneously decreased with exenatide. Conclusions: Acute treatment with exenatide blunted the postprandial vasodilatory effect of a high-fat meal in prediabetes. Exenatide's acute effects derived primarily from multiple endothelium-independent processes. Trial Registration Number: NCT02104739.

Keywords: endothelium; exenatide; postprandial; prediabetes; vasodilation.

Conflict of interest statement

A.D.G. previously served on the Speakers' Bureau for AstraZeneca Pharmaceuticals. No competing financial interests exist for any of the other authors.

Figures

FIG. 1.

Flowchart of participant enrollment, randomization, allocation, follow up, and analysis.

FIG. 2.

Changes of resting and peak FBF in prediabetes subjects after high-fat meal. Data are expressed as mean ± SEM; ○, exenatide; ▲, saxagliptin; ●, placebo; *P < 0.005 exenatide versus placebo; †P < 0.01 versus baseline. n = 15. FBF, forearm blood flow.

FIG. 3.

Changes of plasma nitrotyrosine, 8-iso-PGF2a, triglycerides, total cholesterol, insulin, FFAs, and glucose in prediabetes subjects after high-fat meal. Data are expressed as mean ± SEM; ○, exenatide; ▲, saxagliptin; ●, placebo. *P < 0.05 exenatide versus placebo, ≈P < 0.05 exenatide versus saxagliptin, †P < 0.05 versus baseline. n = 15. 8-iso-PGF2a = 8-iso-prostaglandin F2alpha. FFA, free fatty acid.

FIG. 4.

(Left) Relationships between postprandial changes (0 to 3 hr) in insulin level and resting FBF in prediabetes subjects after high-fat meal in the exenatide group. (Right) Relationships between postprandial changes (3 to 6 hr) in insulin level and resting FBF in prediabetes subjects after high-fat meal in the exenatide group.

FIG. 5.

(Left) Relationships between postprandial changes (0 to 3 hr) in triglyceride level and resting FBF in prediabetes subjects after high-fat meal in the exenatide group. (Right) Relationships between postprandial changes (3 to 6 hr) in triglyceride level and resting FBF in prediabetes subjects after high-fat meal in the exenatide group.